This randomized phase III trial studies combination chemotherapy to see how well it works compared to combination chemotherapy with topotecan hydrochloride in treating patients with non-metastatic extracranial Ewing sarcoma. Drugs used in chemotherapy, such as vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, ifosfamide, etoposide, and topotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. It is not yet known whether combination chemotherapy is more effective with topotecan hydrochloride in treating Ewing sarcoma.

EFS [ Time Frame: Time from study enrollment to disease progression, appearance of disease at sites considered previously uninvolved, diagnosis of a second malignant neoplasm, death or last patient contact, assessed up to 5 years ] [ Designated as safety issue: No ]

Overall survival [ Time Frame: Time from study enrollment to death or last patient contact, assessed up to 5 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Relative risk for death [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

Estimated using the stratified partial likelihood for the relative risk regression model accounting for the factors used to stratify randomization at the time full information is obtained for the EFS comparison. Methods for censored survival data, including but not limited to log-rank comparisons and proportional hazards regression modeling will be used to assess prognostic significance.

Histological response, in terms of event free survival after local control in patients who received local control therapy [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

Methods for censored survival data, including but not limited to log-rank comparisons and proportional hazards regression modeling will be used.

Positron emission tomography (PET)-determined response, in terms of event free survival after local control [ Time Frame: Up to week 13 ] [ Designated as safety issue: No ]

Methods for censored survival data, including but not limited to log-rank comparisons and proportional hazards regression modeling will be used.

Probabilities of identifying tumors of at least 200 ml [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

A two sided log-rank test of size 0.05 as a function of the percent of patients for whom measurements can be obtained will be used.

Extent of tumor necrosis according to the necrosis grading criteria in patients who have surgical resection of tumor [ Time Frame: Week 13 ] [ Designated as safety issue: No ]

The probabilities of identifying patients with 'standard' necrosis grading as associated with increased risk using a two sided log-rank test of size 0.05 as a function of the percent of patients with 'standard' necrosis grading and its associated relative risk will be used.

Radiological response of soft tissue component of mass by PET [ Time Frame: Up to week 13 ] [ Designated as safety issue: No ]

The probabilities of identifying patients with complete response (CR) as associated with decreased risk for EFS-event when compared with patients with less-than-CR using a two sided log-rank test of size 0.05 as a function of the percent of patients with standard response and its associated relative risk will be used.

Differences associated with local control modality on risk for EFS event, according to surgery only v. radiation therapy only v. surgery and radiation therapy [ Time Frame: Up to week 13 ] [ Designated as safety issue: No ]

Stratified according to primary site of tumor as pelvis v. bone but not pelvis v. extra-osseous site. An omnibus log-rank test of size 0.05 will be used to assess whether there are differences associated with local control modality.

Number and proportion of patients who experience any grade 2 or higher musculoskeletal event (ME), or surgery required to treat a complication of local therapy [ Time Frame: Up to 3 months post-local control therapy ] [ Designated as safety issue: Yes ]

Will be based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The proportion of patients who experience any ME will be compared across the three regimens using an exact test of proportions of size 0.05.

Proportion of patients who have tumor present at the margin of resection on risk for EFS event in patients undergoing surgery [ Time Frame: Week 13 ] [ Designated as safety issue: No ]

INDUCTION THERAPY: Patients receive vincristine sulfate (IV) on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV on days 1 and 2 and cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 5, and 9; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 7, and 11.

INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, 10, 11 and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1 and 9, and on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm I; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 5 and 11.

CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7-10, 13-16, 19, and 20; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1, 7, and 15; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1, 7, and 15, and on day 1 in weeks 9, 13, and 19; ifosfamide IV over 1 hour and etoposide IV over 1- 2 hours on days 1-5 in weeks 3, 5, 11, 17, and 21; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 9,13, and 19.

For the purpose of this study, chest wall tumors with ipsilateral pleural effusions, ipsilateral positive pleural fluid cytology or ipsilateral pleural based secondary tumor nodules will be considered localized disease

Patients with regional node involvement, based on clinical suspicion confirmed by pathologic documentation are considered to be non-metastatic

Patients with discontinuous osseous lesions within the same bone are considered to be non-metastatic

Tumors arising in the bony skull (extra-dural) are considered to be extracranial

Patient eligibility will be based on a diagnosis of Ewing sarcoma or PNET by institutional pathologist

No prior chemotherapy or radiation therapy is allowed; patients should only have had a biopsy of the primary tumor without an attempt at complete or partial resection; patients will still be eligible if unplanned excision was attempted or accomplished as long as adequate imaging was obtained prior to surgery

Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by radionuclide angiogram

Exclusion Criteria:

Patients must have no evidence of metastatic disease; metastatic disease:

Are lesions which are discontinuous from the primary tumor, are not regional lymph nodes and do not share a body cavity with the primary tumor; if there is any doubt whether lesions are metastatic, a biopsy of those lesions should be taken

Skeletal lesions in adjacent bones (trans-articular)

Contralateral pleural effusion and contralateral pleural nodules

Distant lymph node involvement

Patients with pulmonary nodules are considered to have metastatic disease if the patient has:

Biopsies of solitary nodule =< 0.5 cm or multiple nodules =< 0.3 cm are not required but if performed and positive indicate metastatic disease

Patients whose tumors arise in the dural and intra-dural soft tissues of the cranium and spine are not eligible

Patients with pathologic diagnoses other than Ewing sarcoma will be excluded

Patients diagnosed with Ewing Sarcoma as a second malignant neoplasm are not eligible if they have received chemotherapy or radiation for the treatment of their primary malignancy

Pregnant women will not be entered on this study; pregnancy tests must be obtained in female patients who are post-menarchal; lactating females may not participate unless they have agreed not to breastfeed their infants; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of the study treatment

All patients and/or their parents or legal guardians must sign a written informed consent

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01231906